11-64635451-GGG-TGA

Variant names:

• chr11-64635451-GGC-TGA
• NM_015080.4:c.3404-1_3405delGCCinsTCA
• NRXN2 p.1136

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_015080.4(NRXN2):​c.3404-1_3405delGCCinsTCA​(p.1136) variant causes a splice acceptor, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRXN2 NM_015080.4 splice_acceptor, splice_region, synonymous, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95
• Publications: 0 publications found

Genes affected

NRXN2 (HGNC:8009): (neurexin 2) This gene encodes a member of the neurexin gene family. The products of these genes function as cell adhesion molecules and receptors in the vertebrate nervous system. These genes utilize two promoters. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms while a smaller number of transcripts are produced from the downstream promoter and encode beta-neuresin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins. Alternative splicing and the use of alternative promoters may generate thousands of transcript variants (PMID: 12036300, PMID: 11944992).[provided by RefSeq, Jun 2010]

NRXN2 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.035415452 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of 3, new splice context is: tttccttctctctgcatcAGgga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	NM_015080.4	MANE Select	c.3404-1_3405delGCCinsTCA	p.1136	splice_acceptor splice_region synonymous intron	N/A	NP_055895.1	Q9P2S2-1
	NRXN2	NM_138732.3		c.3284-1_3285delGCCinsTCA	p.1096	splice_acceptor splice_region synonymous intron	N/A	NP_620060.1	Q9P2S2-2
	NRXN2	NM_001376262.1		c.3404-1_3405delGCCinsTCA	p.1136	splice_acceptor splice_region synonymous intron	N/A	NP_001363191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRXN2	ENST00000265459.11	TSL:5 MANE Select	c.3404-1_3405delGCCinsTCA	p.1136	splice_acceptor splice_region synonymous intron	N/A	ENSP00000265459.5	Q9P2S2-1
	NRXN2	ENST00000704782.1		c.3413-1_3414delGCCinsTCA	p.1139	splice_acceptor splice_region synonymous intron	N/A	ENSP00000516031.1	A0A994J5C3
	NRXN2	ENST00000377559.7	TSL:1	c.3284-1_3285delGCCinsTCA	p.1096	splice_acceptor splice_region synonymous intron	N/A	ENSP00000366782.3	Q9P2S2-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-64402923;